Abelson tyrosine kinase facilitates Salmonella enterica serovar Typhimurium entry into epithelial cells.
The intracellular gram-negative bacterial pathogen Salmonella enterica serovar Typhimurium gains entry into nonphagocytic cells by manipulating the assembly of the host actin cytoskeleton. S. enterica serovar Typhimurium entry requires a functional type III secretion system, a conduit through which bacterial effector proteins are directly translocated into the host cytosol. We and others have previously reported the enhancement of tyrosine kinase activities during Salmonella serovar Typhimurium infection; however, neither specific kinases nor their targets have been well characterized. In this study, we investigated the roles of the cellular Abelson tyrosine kinase (c-Abl) and the related protein Arg in the context of serovar Typhimurium infection. We found that bacterial internalization was inhibited by more than 70% in cells lacking both c-Abl and Arg and that treatment of wild-type cells with a pharmaceutical inhibitor of the c-Abl kinase, STI571 (imatinib), reduced serovar Typhimurium invasion efficiency to a similar extent. Bacterial infection led to enhanced phosphorylation of two previously identified c-Abl substrates, the adaptor protein CT10 regulator of kinase (CrkII) and the Abelson-interacting protein Abi1, a component of the WAVE2 complex. Furthermore, overexpression of the nonphosphorylatable form of CrkII resulted in decreased invasion. Taken together, these findings indicate that c-Abl is activated during S. enterica serovar Typhimurium infection and that its phosphorylation of multiple downstream targets is functionally important in bacterial internalization.
Ly
Kim Thien
KT
Department of Microbiology, University of Virginia Health System, Charlottesville, Virginia 22908-0732, USA.
Casanova
James E
JE
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D001549:Benzamides; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004847:Epithelial Cells / Q000382:microbiology*; D006367:HeLa Cells; D006801:Humans; D000068877:Imatinib Mesylate; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors / Q000502:physiology*; D050737:Proto-Oncogene Proteins c-crk / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D012485:Salmonella typhi / Q000472:pathogenicity*
C513733:ABI1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D001549:Benzamides; D003598:Cytoskeletal Proteins; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D050737:Proto-Oncogene Proteins c-crk; D011743:Pyrimidines; D000068877:Imatinib Mesylate; C426236:ARG tyrosine kinase; D011505:Protein-Tyrosine Kinases; D016315:Proto-Oncogene Proteins c-abl